Compelling evidence suggests that oligomeric A? plays a crucial neurotoxic and synaptotoxic role in Alzheimer?s disease (AD), and that hyperphosphorylation of the microtubule associated protein (MAP) tau mediates or facilitates A? toxicity. The nature of the link between A? and tau in causing AD has however remained largely unexplained, casting doubt on the amyloid hypothesis itself. In neurons, control of microtubule dynamics and tubulin modifications that accumulate on stable microtubules is necessary for multiple homeostatic and regulated functions, including long-distance transport and synaptic activity. Thus, regulation of the ratio between stable and dynamic microtubules is crucial to avoid disease. To date, almost nothingisknownaboutwhetherinductionofhyperstableandmodifiedmicrotubulesisaprimaryactivityofA? thatcontributestotauhyperphosphorylationandsynaptotoxicity. We have preliminary data that detyrosinated tubulin is enriched in hippocampal tissue of AD patients andanimalmodelsofAD,andthataccumulationofdetyrosinatedtubulinmayinducetauhyperphosphorylation in primary neurons. In addition, we found that acute incubation of primary neurons with oligomeric A?1-42 generated detyrosinated MTs by transient microtubule hyperstabilization. Inhibition of the formin mDia1, a positive regulator of microtubule stability, suppressed this activity, affected tau hyperphosphorylation and rescuedsynaptotoxicityinducedbyA?invitro.Theoverallobjectiveofthisproposalistotesttheparadigm- shifting hypothesis that oligomeric A? acutely induces hyperstable detyrosinated microtubules through the activation of mDia1, and that tubulin detyrosination contributes to tau hyperphosphorylation as part of a negative feedback loop to maintain appropriate levels of dynamic and unmodified microtubules. In this proposal,wewillcharacterizethenatureofthismicrotubulehyperstabilizationinneuritesandatsynapticsites, and investigate whether APP and integrin signaling pathways are required for this A?-driven microtubule activity. In addition, we will test the role of mDia1 in mediating A?-synaptotoxicity in vivo, and examine the molecularmechanismsbywhichmDia1-synaptotoxicityoccurs. Ourproposalreliesonamultidisciplinaryefforttotestapathogenicroleforformin-mediatedregulation of microtubule stability by A? and the involvement of tubulin detyrosination in the induction of tau hyperphosphorylation and neuronal injury. Our studies will test a unifying theory for the pathogenesis of AD and examine the role for mDia1 and possibly other formins as potential targets in drug therapies aimed at rescuingA?andphospho-tautoxicityinAD.